EP0257956B2 - Usage de facteurs de croissance et de cytocines polypeptides pour fabriquer un dispositif et une dispersion - Google Patents

Usage de facteurs de croissance et de cytocines polypeptides pour fabriquer un dispositif et une dispersion Download PDF

Info

Publication number
EP0257956B2
EP0257956B2 EP87307276A EP87307276A EP0257956B2 EP 0257956 B2 EP0257956 B2 EP 0257956B2 EP 87307276 A EP87307276 A EP 87307276A EP 87307276 A EP87307276 A EP 87307276A EP 0257956 B2 EP0257956 B2 EP 0257956B2
Authority
EP
European Patent Office
Prior art keywords
polypeptide
particles
use according
cytokines
pulmonary
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP87307276A
Other languages
German (de)
English (en)
Other versions
EP0257956A3 (en
EP0257956B1 (fr
EP0257956A2 (fr
Inventor
Ann Leslie Daugherty
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Original Assignee
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25408720&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP0257956(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Genentech Inc filed Critical Genentech Inc
Priority to AT87307276T priority Critical patent/ATE76311T1/de
Publication of EP0257956A2 publication Critical patent/EP0257956A2/fr
Publication of EP0257956A3 publication Critical patent/EP0257956A3/en
Publication of EP0257956B1 publication Critical patent/EP0257956B1/fr
Application granted granted Critical
Publication of EP0257956B2 publication Critical patent/EP0257956B2/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/217—IFN-gamma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06—Sprayers or atomisers specially adapted for therapeutic purposes of the injector type

Definitions

  • This invention relates to the administration of proteins by adsorption from the lungs.
  • it is concerned with providing therapeutic, sustained doses of growth hormones or cytokines to the bloodstream without irritating or otherwise damaging lung tissues.
  • Drug delivery by pulmonary absorption from particles such as aerosols has met with considerable success in several instances of localized delivery to lungs as the drug target tissue, most notably the use of beta adrenergic antagonists in the treatment of asthma.
  • Other drugs that have been administered in this fashion include corticosteroids and cromolyn sodium.
  • the administration of aminoglycoside antibiotics, antiviral drugs and anti-cancer drugs for systemic action by this route has only met with spotty success.
  • lack of delivery to the blood stream was attributed to inability of the drug to pass through the alveolar epithelium.
  • the drug was found to be irritating and bronchoconstrictive (Juliano, 1984, "Pharm. Ther.”, 24 :355-365). At this time it is not possible to reasonably predict in advance that any given drug will be nonirritating or will be adsorbed through the lungs in an amount sufficient to be therapeutically useful.
  • polypeptide probes besides albumin, gamma globulin and HRP have been used in the study of pulmonary absorption. These include microperoxidase, equine cytochrome c , equine myoglobin, bovine lactoperoxidase and human myeloperoxidase (Schneeberger, 1978, “Fed. Proc.” 37 (11):2471), superoxide dismutase or catalase (Padmanabhan et al ., 1985, "Am. Rev. Respir. Dis.” 132 (1):164-167), and ferritin (Richardson et al ., 1976, "Lab. Invest.” 35 (4):307). None of these agents, however, has been employed in a systemic therapeutic context, i.e. delivered in the expectation of achieving a therapeutic dosage at a desired site distal from the lungs per se .
  • U.S. Patent 4,476,116 proposes delivering human growth hormone or interferon by intranasal absorption of a nasal spray containing the protein and a chelating agent. Since particles of 5 ⁇ m or greater are removed in the nasopharyngeal region (Juliano et al .) It must be concluded that an effective nasal spray would contain aerosol particles having at least this mean diameter.
  • EP 122036 describes a powdered composition for intranasal administration of growth hormone or interferon wherein at least 90% of the particles had an effective diameter of 10 to 250 Microns. The minimum diameter was established with the object to avoid introducing the particles into the lungs.
  • Intranasal administration of growth hormone or interferons is undesirable because of dosage variability, side effects such as nasal irritation, extremely poor polypeptide permeability into the blood stream and polypeptide degradation by normal nasal microorganisms.
  • these polypeptides have been conventionally administered by injection or infusion. This delivery route suffers from obvious deficiencies, the most glaring being the requirement for regular growth hormone injections in children or, in the case of interferons being employed for the treatment of malignancies, an absence of a healthy vasculature for catheterisation of the patients. An improved method for the administration of these proteins is needed.
  • European patent application EP-A1-0 170 715 discloses an atomising apparatus intended to produce a high proportion of aerosol particles whose size lies between 0.5 and 5.5 ⁇ m.
  • the apparatus disclosed is suitable for atomising powders and liquids. No details of the composition of the material to be atomised is given.
  • the present invention provides claim 1 Another aspect of the invention provides (claim 10).
  • An advantage with respect to the delivery of therapeutic doses of these particular polypeptides is that they are delivered systemically by pulmonary absorption without pathological effects on the lungs or a requirement for an epithelial irritant or absorption enhancing agent such as ether, zinc oxide, antigens, histamine, methacholine, water soluble amphophilic steroids, bile salts such as sodium glycocholate, lower alkyl ethers of cellulose, chelating agents or water absorbing-water insoluble substances such as polyvinyl pyrrolidone, sodium carboxymethyl cellulose, polyacrylates and the like.
  • an epithelial irritant or absorption enhancing agent such as ether, zinc oxide, antigens, histamine, methacholine, water soluble amphophilic steroids, bile salts such as sodium glycocholate, lower alkyl ethers of cellulose, chelating agents or water absorbing-water insoluble substances such as polyvinyl pyrrolidone, sodium carboxymethyl
  • the polypeptides to be delivered by intrapulmonary absorption are growth factors and cytokines.
  • Growth factors or hormones are polypeptides that induce the proliferation or enlargement of target cells.
  • Such factors are hormones, hereafter referred to as hormones for convenience, may incidentally increase the respiratory rate or metabolism of the target cells, but in the absence of increased cell mitosis or enlargement a polypeptide is not to be considered a growth hormone for the purposes of this application.
  • Most growth hormones exhibit a molecular weight of about from 5 kD to 75 kD and a pI ranging from about 4 to 8.
  • growth hormone thymosin
  • somatomedins such as IGF-1 or IGF-2
  • transforming growth factors- ⁇ and ⁇ nerve growth factor, platelet-derived growth factor, ovarian growth factor, fibroblast growth factor, myoblast growth factor, epidermal growth factor and the like, but excluding insulin.
  • IGF-1 or IGF-2 growth hormone
  • transforming growth factors- ⁇ and ⁇ nerve growth factor
  • platelet-derived growth factor ovarian growth factor
  • fibroblast growth factor fibroblast growth factor
  • myoblast growth factor myoblast growth factor
  • epidermal growth factor epidermal growth factor and the like
  • Cytokines are the polypeptide secretory products of cells constituting the immune system, e.g. lymphocytes such as B-cells and T cells, including helper and suppressor T cells, macrophages and neutrophils. Cytokines serve as effectors in that they induce changes in the activity or secretory products of other immune cells, or a direct acting proteins in that they induce a change in a target non-immune cell. Furthermore, many cytokines, e.g. thymosin or gamma interferon, may be considered growth hormones as well in that they induce the proliferation of specialized immune target cells. Typically, cytokines have molecular weights of about from 5 kD to 30 kD and pI of about from 4 to 8.
  • cytokines examples include the interleukins, tumor necrosis factors, interferons and immune suppressor factors.
  • Preferred cytokines for use herein are tumor necrosis factors - ⁇ and ⁇ , and interferons- ⁇ , ⁇ and ⁇ .
  • growth hormone and cytokine are to be considered to include amino acid sequence, glycosylation and other variants of the native molecules. These variants may exhibit enhanced levels of the normal biological activity of the native molecules or may, on the contrary, act antagonistically towards the native molecule. Alternatively, variant are selected for improved characteristics such as stability to oxidation, extended biological half-life, and the like. Such variants as are known or will be developed in the future are suitable for use herein.
  • N-terminal methionyl human growth hormone (somatrem) is an example of a common variant produced in recombinant cell culture wherein a methionine residue not found in the native analogue is covalently bound to the normal N-terminal amino acid residue.
  • polypeptides administered in accordance with this invention are first placed into a particulate dispersed form. This is accomplished by preparing an aqueous aerosol or solid particles which contain the polypeptide. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the desired polypeptide together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers will vary depending upon the requirements for each polypeptide, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • the formulations also can include mucolytic agents such as those described in U.S. Patent 4,132,803, as well as bronchodilating agents.
  • the formulations will be sterile. Aerosols generally will be prepared from isotonic solutions.
  • the particles optionally include normal lung surfactant proteins.
  • aerosols of particles in aqueous or nonaqueous, e.g. fluorocarbon propellant, suspension Such particles include, for example, intramolecular aggregates of the polypeptides or liposomal or microcapsular-entrapped polypeptides.
  • the aerosols should be free of lung irritants, i.e. substances which cause acute bronchoconstriction, coughing, pulmonary edema or tissue destruction.
  • nonirritating absorption enhancing agents are suitable for use herein.
  • the dispersing means may be means for hydraulic atomization or for ultrasonic dispersion.
  • Sonic nebulizers preferably are used in preparing aerosols. Sonic nebulizers minimize exposing the polypeptides to shear which can result in degradation of the molecule.
  • a suitable device is the Bird Micronebulizer.
  • Particulate aerosol suspensions are essentially fine dry powders containing the polypeptides. They are prepared by any number of conventional procedures. The simplest method of producing them is to micronize polypeptide, e.g. crystals or lyophilization cakes, and suspend the particles in dry fluorocarbon propellants. In these formulations the polypeptides do not dissolve in the hydrophobic propellants (which evaporate after the suspension is released from the pressurized device into the air). Rather, the polypeptides are suspended in the fluorocarbon. In an alternate embodiment the polypeptides are stored in a compartment separate from the propellant. Discharge of the propellant withdraws a predetermined dose from the storage compartment. The devices used to deliver drugs in this manner are known as metered dose inhalers (MDIs) (P.R. Byron, 1986, “Drug Development and Industrial Pharmacy” 12 :993).
  • MDIs metered dose inhalers
  • the size of the aerosols or particles generally will range about from 0.5 ⁇ m to 4 ⁇ m, preferably about 0.5 to 1 ⁇ m. Smaller particles are less acceptable because they tend not to be deposited but instead are exhaled. Larger particles are not preferred because in large measure are unable to be deposited at the level of the alveoli, being removed by impaction within the nasopharyngeal or oral cavities (Byron, 1986, "J. Pharm. Sci.” 75 :433). Obviously, most aerosol or particulate compositions will be heterogenous in size distribution, although heterogeneity can be reduced by known methods, e.g. the screening unit described in EP 135390A.
  • Heterogeneity will not be disadvantageous unless the proportion of particles having an average mean diameter in excess of about 4 ⁇ m is so large as to impair the delivery of a therapeutic dose by pulmonary inhalation.
  • Suspensions containing greater than about 15% of particles within the 0.5-4 ⁇ m range can be used, but generally the proportion of particles having an average mean diameter larger than 4 ⁇ m should be less than about 25%, and preferably not greater than 10%, of the total number of particles.
  • the diameters recited refer to the particle diameters as introduced into the respiratory tract.
  • the particles may or may not bear a net charge.
  • the presence of a net charge is desirable for minimizing particle aggregation in the airways since the particles will repel one another electrostatically.
  • Charged particles are made by removing water from solutions of the polypeptides at a pH other than the isoelectric point, e.g. ordinarily about from 0.5 to 2 pH units on either side of the isoelectric point.
  • dewatering of polypeptides at a pH other than the isoelectric point may result in precipitation or denaturation of the protein, so the desirability of use of such a pH will depend upon the known characteristics of the polypeptide to be administered.
  • FIG. 1 A suitable system for inhalation delivery of the polypeptides herein is illustrated in Fig. 1.
  • a source of compressed air 1 communicates with a nebulizer shown generally at 4 by way of a conduit 2 .
  • the flow of compressed air is controlled by valve 3 .
  • the nebulizer 4 contains a capillary tube 7 which extends down into the solution of growth hormone or cytokine in reservoir 8 .
  • the end of capillary 7 which is distal to solution reservoir 8 terminates immediately adjacent to the orifice 5 of conduit 2 .
  • An impaction sphere 6 is adjustably positioned opposite orifice 5 .
  • the orifice 5 , capillary 7 and sphere 6 serve as the dispering means for forming the aerosol of the polypeptide disposed in reservoir 8 .
  • Nebulizer 4 also includes serrated output baffles shown generally at 9 , downstream of which is a conduit 10 communicating with a respirator mouthpiece 12 for sealably engaging the mouth of the patient (not shown).
  • the passage of aerosol 15 through conduit 10 is controlled by valve 11 , which also operates valve 3 through circuit 13 and control device 14 .
  • compressed air is valved by valve 3 on demand as determined by programmed control device 14 .
  • the control device is actuated on demand from valve 11 .
  • Compressed air passes through conduit 2 and out the orifice 5 .
  • the flow of air over the end of capillary 7 draws the solution of polypeptide from reservoir 8 into the stream of air where, together with collision on the impaction sphere 6 , an aerosol of the solution is formed.
  • the stable aerosol suspension is forced out by air pressure through baffles 9 and down conduit 10 upon demand from valve 11 as activated by the patient.
  • the baffles are selected of appropriate size, dimension and composition to remove the bulk of particles greater than about 4 ⁇ m.
  • the seating of mouthpiece 12 will ensure that the patient inhales substantially only the delivered mixture of air and aerosolized polypeptide with each breath.
  • a Bird Micronebulizer in line with Bird Mark 7 respirator was charged with 5-10 ml of a solution of 12 mg/ml Protropin R brand of met-hGH (somatrem) in mannitol/phosphate buffer. The Micronebulizer then was used to simultaneously ventilate and dose the animal at 22 cm H 2 O at a rate of 1.8 mg/hGH/-min. for 30 min. At this pressure the animal ventilated at approximately normal inspiratory volume.
  • the animal was allowed to exhale normally after each ventilated breath and was positioned supine for dosing. After the first dosing period the animal was allowed to breathe normally for another 20 minutes, after which a second dosing was performed in the same way as the first. Blood plasma samples were taken at the initiation time of the first dose and thereafter as shown by the data points in Fig. 2. The baboon completely emerged from anesthesia 8 hours after the last pentobarbital injection. Radioimmunoassays of met-hGH in these sera showed that intrapulmonary delivery in accord herewith produced a blood level that is greater than twice that which is considered an acceptable therapeutic dose when administered intramuscularly.
  • the radioimmunoassay employed in this example also will cross-react with normal baboon growth hormone, so it is believed that some of the hGH detected at 28 hours after the commencement of dosing may represent a circadian or stress induced increase in baboon growth hormone, probably similar to the levels in rhesus monkeys (10 ng/ml). Since the normal detectable GH levels in primates typically fall within the 10-20 ⁇ g/ml range, the method of this invention made it possible to deliver far in excess of a systemic therapeutically effective dose of hGH for a period exceeding 28 hours. This was particularly surprising since the general view is that long term drug delivery (>12 hr) is not achievable by intrapulmonary inhalation (Byron, op cit .).
  • polypeptides By means of the present invention it is possible to administer these polypeptides without the need for injections or infusions of certain polypeptides. This reduces the frequency of administration by providing sustained release from pulmonary tissue. It also enables therapeutically effective doses of the polypeptides to be delivered without therapeutically significant degradation of the polypeptides or the use of agents that lead to irritation of the bronchi, epithelium or other pulmonary tissue.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Otolaryngology (AREA)
  • Dispersion Chemistry (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Claims (17)

  1. Utilisation d'un polypeptide choisi entre des facteurs de croissance et des cytokines pour la production d'un dispositif destiné à délivrer au flux sanguin d'un patient une dose thérapeutique du peptide par administration générale par absorption pulmonaire, ledit dispositif comprenant un moyen servant de réservoir (8) pour le stockage du polypeptide ; une forme posologique thérapeutique du polypeptide placée dans le réservoir ; des moyens de dispersion (4 - 7) pour la mise sous forme de gaz d'une suspension de particules comprenant le polypeptide, plus d'environ 15 % des particules ayant un diamètre moyen compris approximativement dans l'intervalle de 0,5 µm à 4 µm ; des moyens (1 - 3) pour le transport du polypeptide aux moyens de dispersion et des moyens (9 - 12) pour délivrer la suspension de particules aux alvéoles des poumons du patient.
  2. Utilisation suivant la revendication 1, dans laquelle la proportion de particules ayant un diamètre moyen supérieur à environ 4 µm est inférieure à environ 25 %.
  3. Utilisation suivant la revendication 1 ou la revendication 2, dans laquelle le polypeptide est la somatotrophine, le somatrème, l'interleukine 1, l'interleukine 2, le facteur α de nécrose tumoral, le facteur β de nécrose de tumeur, une association du facteur α de nécrose de tumeur ou du facteur β de nécrose de tumeur plus un interféron ; ou bien une association d'un interféron et d'interleukine 2.
  4. Utilisation suivant l'une quelconque des revendications 1 à 3, dans laquelle le réservoir (8) contient une solution aqueuse du polypeptide.
  5. Utilisation suivant l'une quelconque des revendications 1 à 3, dans laquelle le réservoir (8) contient une poudre comprenant le polypeptide en suspension dans un hydrocarbure fluoré anhydre.
  6. Utilisation suivant l'une quelconque des revendications 1 à 5, dans laquelle les moyens d'administration (12) sont aptes à délivrer la dose aux alvéoles des poumons sans un contact notable avec les voies nasales.
  7. Utilisation suivant la revendication 6, dans laquelle les moyens pour délivrer la suspension aux alvéoles consistent en un embout (12) destiné à être introduit de manière étanche dans la cavité buccale.
  8. Utilisation suivant l'une quelconque des revendications 1 à 7, dans laquelle le polypeptide n'est pas accompagné d'un agent accroissant l'absorption.
  9. Utilisation d'un polypeptide choisi entre des facteurs de croissance et des cytokines pour la production d'une dispersion dudit polypeptide afin de délivrer au flux sanguin d'un patient une dose thérapeutique du polypeptide par administration générale par absorption pulmonaire, ladite dispersion contenant des particules dans lesquelles plus d'environ 15 % des particules ont un diamètre moyen d'environ 0,5 à 4 µm.
  10. Utilisation suivant la revendication 9, dans laquelle les particules contiennent une solution aqueuse du polypeptide.
  11. Utilisation suivant la revendication 10, dans laquelle la dispersion est dépourvue d'un éther, d'antigènes, d'histamines, d'oxyde de zinc, de méthacholine, de stéroïdes amphophiles, d'agents chélatants, de sels biliaires ou de polymères insolubles dans l'eau et absorbant l'eau, en des quantités suffisantes pour accroítre l'absorption.
  12. Utilisation suivant l'une quelconque des revendications 9 à 11, dans laquelle approximativement 75 à 100 % des particules possèdent un diamètre moyen d'environ 0,5 à 4 µm.
  13. Utilisation suivant l'une quelconque des revendications 9 à 12, dans laquelle les particules ne sont pas des liposomes ou des microcapsules.
  14. Utilisation suivant l'une quelconque des revendications 9 à 13, dans laquelle les particules consistent en une solution aqueuse, transformée en un aérosol, du facteur de croissance et/ou de la cytokine.
  15. Utilisation suivant la revendication 14, dans laquelle la solution est pratiquement isotonique.
  16. Utilisation suivant l'une quelconque des revendications 9 à 15, qui est dépourvue d'irritants pulmonaires.
  17. Utilisation suivant l'une quelconque des revendications 9 à 16, dans laquelle les particules contiennent un surfactant pulmonaire.
EP87307276A 1986-08-19 1987-08-18 Usage de facteurs de croissance et de cytocines polypeptides pour fabriquer un dispositif et une dispersion Expired - Lifetime EP0257956B2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87307276T ATE76311T1 (de) 1986-08-19 1987-08-18 Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und zytokinen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US89796286A 1986-08-19 1986-08-19
US897962 1986-08-19

Publications (4)

Publication Number Publication Date
EP0257956A2 EP0257956A2 (fr) 1988-03-02
EP0257956A3 EP0257956A3 (en) 1989-04-19
EP0257956B1 EP0257956B1 (fr) 1992-05-20
EP0257956B2 true EP0257956B2 (fr) 2000-11-22

Family

ID=25408720

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87307276A Expired - Lifetime EP0257956B2 (fr) 1986-08-19 1987-08-18 Usage de facteurs de croissance et de cytocines polypeptides pour fabriquer un dispositif et une dispersion

Country Status (8)

Country Link
US (3) US6099517A (fr)
EP (1) EP0257956B2 (fr)
JP (1) JP2573959B2 (fr)
AT (1) ATE76311T1 (fr)
CA (1) CA1292182C (fr)
DE (1) DE3779221D1 (fr)
ES (1) ES2032831T5 (fr)
GR (1) GR3005238T3 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7744925B2 (en) 1994-12-02 2010-06-29 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US8168223B1 (en) 1997-09-29 2012-05-01 Novartis Pharma Ag Engineered particles and methods of use
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US10507227B2 (en) 2014-04-15 2019-12-17 The Hospital For Sick Children Cationic antimicrobial peptides

Families Citing this family (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3779221D1 (de) * 1986-08-19 1992-06-25 Genentech Inc Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und -zytokinen.
US5037644A (en) * 1986-10-27 1991-08-06 Cetus Corporation Pharmaceutical compositions of recombinant interleukin-2 and formulation processes
US4944941A (en) * 1987-08-07 1990-07-31 Genentech, Inc. Methods and compositions for the treatment of lung conditions
JP2739733B2 (ja) * 1988-08-09 1998-04-15 オムロン株式会社 吸入器
US5198212A (en) * 1988-10-31 1993-03-30 University Of Lousville Research Foundation Incorporated Method and compositions for treatment of trauma-associated sepsis with gamma interferon
EP0377174A3 (fr) * 1988-12-22 1990-11-22 Büsselmann, Manfred Procédé et appareil pour pulvérisation et atomisation de substances liquides
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
JPH05963A (ja) * 1990-04-13 1993-01-08 Toray Ind Inc ポリペプチド類組成物
EP0462305B1 (fr) * 1990-06-21 1994-11-02 Huland, Edith, Dr. Dr. Aérosols contenant des cytokines et leur utilisation
US5780012A (en) * 1990-06-21 1998-07-14 Huland; Edith Method for reducing lung afflictions by inhalation of cytokine solutions
US6565841B1 (en) 1991-03-15 2003-05-20 Amgen, Inc. Pulmonary administration of granulocyte colony stimulating factor
DE4117078A1 (de) * 1991-05-25 1992-11-26 Boehringer Ingelheim Kg Verfahren zur herstellung therapeutisch anwendbarer aerosole
US6673335B1 (en) 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
US6024090A (en) * 1993-01-29 2000-02-15 Aradigm Corporation Method of treating a diabetic patient by aerosolized administration of insulin lispro
US7448375B2 (en) * 1993-01-29 2008-11-11 Aradigm Corporation Method of treating diabetes mellitus in a patient
US5354934A (en) † 1993-02-04 1994-10-11 Amgen Inc. Pulmonary administration of erythropoietin
IL109350A (en) * 1993-05-12 2001-01-28 Genentech Inc Stable liquid preparations of gamma interferon
US5497763A (en) * 1993-05-21 1996-03-12 Aradigm Corporation Disposable package for intrapulmonary delivery of aerosolized formulations
US5512269A (en) * 1993-06-09 1996-04-30 Burroughs Wellcome, Co. Method of treating retained pulmonary secretions
US20030113273A1 (en) * 1996-06-17 2003-06-19 Patton John S. Methods and compositions for pulmonary delivery of insulin
AU689217B2 (en) * 1994-03-07 1998-03-26 Novartis Ag Methods and compositions for pulmonary delivery of insulin
US5522385A (en) * 1994-09-27 1996-06-04 Aradigm Corporation Dynamic particle size control for aerosolized drug delivery
US6428771B1 (en) * 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
US5972331A (en) * 1995-12-22 1999-10-26 Schering Corporation Crystalline interferon alpha for pulmonary delivery and method for producing the same
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US6652837B1 (en) 1996-05-24 2003-11-25 Massachusetts Institute Of Technology Preparation of novel particles for inhalation
DE69939374D1 (de) 1998-03-17 2008-10-02 Genentech Inc Zu vegf und bmp1 homologe polypeptide
SE9803770D0 (sv) * 1998-11-05 1998-11-05 Astra Ab Dry powder pharmaceutical formulation
DE19851380A1 (de) * 1998-11-07 2000-05-11 Messer Griesheim Gmbh Parfümierung von Sauerstoff
EP2339003A3 (fr) 1999-06-28 2011-10-19 Genentech, Inc. Polypeptides variants substitutionnels du ligand Apo-2
US9006175B2 (en) * 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
ES2526707T3 (es) * 1999-06-29 2015-01-14 Mannkind Corporation Purificación y estabilización de péptidos y proteínas en agentes farmacéuticos
US6749835B1 (en) 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
US7678364B2 (en) 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
JP3852256B2 (ja) 1999-11-10 2006-11-29 富士ゼロックス株式会社 インクジェット記録装置
JP2001187459A (ja) 1999-12-28 2001-07-10 Fuji Xerox Co Ltd インクジェット記録装置
US20010043906A1 (en) * 1999-12-30 2001-11-22 Vlasselaer Peter Van gamma-IFN liquid-droplet aerosol and method
DE60141680D1 (de) * 2000-01-14 2010-05-12 Univ Brown Res Found Verfahren zur herstellung von mikronisierte gefriergetrocknete partikeln
JP2003524646A (ja) * 2000-01-25 2003-08-19 エアロファーム テクノロジー インコーポレイテッド 医薬エアゾール製剤
US6585957B1 (en) 2000-01-25 2003-07-01 Aeropharm Technology Incorporated Medicinal aerosol formulation
CA2648051A1 (fr) 2000-06-23 2002-01-03 Genentech, Inc. Compositions et procedes de diagnostic et de traitement de troubles dont l'angiogenese
EP2275549A1 (fr) 2000-06-23 2011-01-19 Genentech, Inc. Compositions et procédés pour le traitement et le diagnostic des troubles impliquant une angiogénèse
CA2418960A1 (fr) 2000-08-07 2002-02-14 Inhale Therapeutic Systems, Inc. Poudres a inhaler de proteines en faisceau a quatre helices sechees par atomisation presentant une agregation reduite au minimum
JP4931282B2 (ja) * 2000-10-02 2012-05-16 日本ケミカルリサーチ株式会社 生理活性ペプチド含有粉末
AU2002217880A1 (en) * 2000-11-15 2002-05-27 Scimed Life Systems, Inc. Device and method for treating female urinary incontinence
AU2002230993B2 (en) 2000-12-29 2006-02-02 Alkermes, Inc. Particles for inhalation having sustained release properties
EP1430136A1 (fr) * 2001-09-27 2004-06-23 Pieris ProteoLab AG Muteines d'apolipoproteine d
WO2003029462A1 (fr) * 2001-09-27 2003-04-10 Pieris Proteolab Ag Muteines de la lipocaline neutrophile humaine associee a la gelatinase et de proteines apparentees
JP2005508162A (ja) 2001-10-02 2005-03-31 ジェネンテック・インコーポレーテッド Ａｐｏ−２リガンド変異体とその使用法
EP2322165A1 (fr) 2001-11-13 2011-05-18 Genentech, Inc. Compositions à base de Apo2 ligand/TRAIL
WO2003055730A1 (fr) 2001-12-27 2003-07-10 Nsk Ltd. Levier de direction de type a basculement de vehicule
US20040063912A1 (en) * 2002-03-15 2004-04-01 The Brigham And Women's Hospital, Inc. Central airway administration for systemic delivery of therapeutics
CA2478327A1 (fr) * 2002-03-20 2003-10-02 Advanced Inhalation Research, Inc. Preparations d'hormone de croissance humaine (hch) destinees a etre administrees par voie pulmonaire
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
US7008644B2 (en) * 2002-03-20 2006-03-07 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
SI1494732T1 (sl) 2002-03-20 2008-08-31 Mannking Corp Inhalacijski aparat
EP2305710A3 (fr) 2002-06-03 2013-05-29 Genentech, Inc. Bibliothèques de phages et anticorps synthétiques
EP1556076A4 (fr) 2002-06-24 2009-07-08 Genentech Inc Variants du ligand apo-2/trail et utilisations de ceux-ci
AU2003264917A1 (en) * 2002-07-08 2004-01-23 Pliva - Istrazivacki Institut D.O.O. Hybrid molecules of macrolides with steroid/non-steroid anti-inflammatory, antineoplastic and antiviral active molecules
NZ537717A (en) * 2002-07-08 2006-04-28 Pliva Istrazivacki Inst D New compounds, compositions and methods for treatment of inflammatory diseases and conditions
RS20050300A (en) 2002-10-16 2007-08-03 Euro-Celtique S.A., Antibodies that bind cell-associated ca 125/0772p and methods of use thereof
HRP20030324A2 (en) 2003-04-24 2005-02-28 Pliva-Istra�iva�ki institut d.o.o. Compounds of antiinflammatory effect
US7338171B2 (en) * 2003-10-27 2008-03-04 Jen-Chuen Hsieh Method and apparatus for visual drive control
CN101027082A (zh) * 2004-01-12 2007-08-29 曼恩坎德公司 降低2型糖尿病患者血清胰岛素原水平的方法
PT1740154E (pt) * 2004-03-12 2009-09-11 Biodel Inc Composições de insulina com absorção melhorada
US20080090753A1 (en) * 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
JP5078014B2 (ja) 2004-08-20 2012-11-21 マンカインド コーポレイション ジケトピペラジン合成の触媒反応
HUE025151T2 (en) 2004-08-23 2016-01-28 Mannkind Corp Diceto-piperazine salts for drug delivery
ATE453658T1 (de) 2004-10-27 2010-01-15 Glaxosmithkline Zagreb Konjugate mit entzündungshemmender aktivität
WO2006055950A1 (fr) * 2004-11-18 2006-05-26 Nektar Therapeutics Formulation pharmaceutique a plusieurs principes actifs
DK1831227T3 (da) * 2004-12-17 2013-08-19 Glenmark Pharmaceuticals Sa Hidtil ukendte, heterocykliske forbindelser, der er anvendelige til behandling af inflammatoriske og allergiske forstyrrelser
WO2006064355A2 (fr) * 2004-12-17 2006-06-22 Glenmark Pharmaceuticals S.A. Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
EP1928423B1 (fr) 2005-09-14 2015-12-09 Mannkind Corporation Procédé de composition de médicament s appuyant sur une augmentation de l affinité d agents actifs pour des surfaces de microparticules cristallines
US7713929B2 (en) 2006-04-12 2010-05-11 Biodel Inc. Rapid acting and long acting insulin combination formulations
WO2007041481A1 (fr) * 2005-09-29 2007-04-12 Biodel, Inc. Preparations d'insuline a action rapide et prolongee
US8084420B2 (en) * 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
EP1986679B1 (fr) 2006-02-22 2017-10-25 MannKind Corporation Procédé pour améliorer les propriétés pharmaceutiques de microparticules comprenant de la dicétopipérazine et un agent actif
JP2009533471A (ja) * 2006-04-12 2009-09-17 バイオデル， インコーポレイテッド 即効型および長時間作用型組合せインスリン製剤
GB0617417D0 (en) * 2006-09-05 2006-10-18 Concept 2 Manufacture Design L A nebuliser valve
WO2008124522A2 (fr) * 2007-04-04 2008-10-16 Biodel, Inc. Formulations contenant de l'amyline
CN101951957A (zh) * 2008-01-04 2011-01-19 百达尔公司 胰岛素释放作为组织的葡萄糖水平的函数的胰岛素制剂
JP4654266B2 (ja) * 2008-05-14 2011-03-16 株式会社群馬コイケ ネブライザー
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
KR101558026B1 (ko) 2008-06-13 2015-10-06 맨카인드 코포레이션 건조 분말 흡입기 및 약물 투여 시스템
CA2728523C (fr) 2008-06-20 2020-03-10 Mannkind Corporation Appareil interactif pour l'etablissement en temps reel d'un profil des efforts d'inhalation
TWI614024B (zh) 2008-08-11 2018-02-11 曼凱公司 超快起作用胰島素之用途
KR20110051245A (ko) 2008-09-10 2011-05-17 제넨테크, 인크. 안구 혈관신생의 억제 방법
AU2009303304A1 (en) 2008-10-10 2010-04-15 Anaphore, Inc. Polypeptides that bind TRAIL-RI and TRAIL-R2
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US9060927B2 (en) * 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
US8538707B2 (en) 2009-03-11 2013-09-17 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
EP2260857A1 (fr) 2009-06-11 2010-12-15 Alfact Innovation Nouvelles applications de HIP/PAP ou dérivés associés
EP2440184B1 (fr) 2009-06-12 2023-04-05 MannKind Corporation Microparticules de dicétopipérazine avec des surfaces spécifiques définies
CA2778698A1 (fr) 2009-11-03 2011-05-12 Mannkind Corporation Appareil et methode de simulation d'efforts d'inhalation
US9549968B2 (en) 2009-12-07 2017-01-24 Pieris Pharmaceuticals Gmbh Muteins of human lipocalin 2 (LcnC,hNGAL) with affinity for a given target
CA2801936C (fr) 2010-06-21 2021-06-01 Mannkind Corporation Systeme et procede d'administration de medicament sous la forme d'une poudre seche
MX2013010185A (es) 2011-03-10 2014-02-17 Genentech Inc Tratamiento de alteraciones con funcion de barrera vascular alterada.
KR101940832B1 (ko) 2011-04-01 2019-01-21 맨카인드 코포레이션 의약 카트리지용 블리스터 패키지
US20140178398A1 (en) 2011-05-03 2014-06-26 Genentech, Inc Vascular disruption agents and uses thereof
WO2012174472A1 (fr) 2011-06-17 2012-12-20 Mannkind Corporation Microparticules de dicétopipérazine de capacité élevée
EP2776053A1 (fr) 2011-10-24 2014-09-17 MannKind Corporation Procédés et compositions pour traiter la douleur
CA2878457C (fr) 2012-07-12 2021-01-19 Mannkind Corporation Systemes et procedes de liberation de medicament en poudre seche
EP2687225A1 (fr) 2012-07-19 2014-01-22 Alfact Innovation Protéine HIP/PAP et ses dérivés pour une utilisation dans le traitement du cancer
EP2911690A1 (fr) 2012-10-26 2015-09-02 MannKind Corporation Compositions et procédés de vaccin antigrippal inhalable
EP2920202B1 (fr) 2012-11-19 2018-08-29 Pieris Pharmaceuticals GmbH Nouveaux polypeptides se liant specifiquement, et leur utilisation
WO2014144895A1 (fr) 2013-03-15 2014-09-18 Mannkind Corporation Compositions de dicétopipérazine microcristallines et procédés
BR122019026637B1 (pt) 2013-07-18 2023-09-26 Mannkind Corporation Formulações farmacêuticas de pó seco e método para a fabricação de uma formulação de pó seco
WO2015021064A1 (fr) 2013-08-05 2015-02-12 Mannkind Corporation Appareil d'insufflation et procédés
US10927154B2 (en) 2014-01-13 2021-02-23 Pieris Pharmaceuticals Gmbh Multi-specific polypeptide useful for localized tumor immunomodulation
WO2015148905A1 (fr) 2014-03-28 2015-10-01 Mannkind Corporation Utilisation d'insuline à action ultrarapide
EP3789397B1 (fr) 2014-05-22 2023-12-06 Pieris Pharmaceuticals GmbH Nouveaux polypeptides de liaison spécifique et leurs utilisations
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
EP3250586B1 (fr) 2015-01-28 2021-10-27 Pieris Pharmaceuticals GmbH Nouvelles protéines spécifiques de l'angiogenèse
WO2016177762A1 (fr) 2015-05-04 2016-11-10 Pieris Pharmaceuticals Gmbh Protéines spécifiques de cd137
CN107636014B (zh) 2015-05-04 2021-12-07 皮里斯制药有限公司 抗癌融合多肽
ES2938525T3 (es) 2015-05-18 2023-04-12 Pieris Pharmaceuticals Gmbh Polipéptido de fusión anticanceroso
EP3298029A1 (fr) 2015-05-18 2018-03-28 Pieris Pharmaceuticals GmbH Mutéines de la lipocaline 2 humaine avec affinité pour glypican-3 (gpc3)
US10703810B2 (en) 2015-11-30 2020-07-07 Pieris Australia Pty Ltd. Fusion polypeptides which bind vascular endothelial growth factor a (VEGF-A) and angiopoietin-2 (Ang-2)
TW201725212A (zh) 2015-12-10 2017-07-16 第一三共股份有限公司 特異性於降鈣素基因相關胜肽的新穎蛋白
WO2023111664A1 (fr) * 2021-12-19 2023-06-22 Kamagtech Bio Pharma Dispositif et méthode applicables au traitement d'agents pathogènes

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4537878A (en) 1981-10-05 1985-08-27 Tni Pharmaceuticals, Inc. Process for using endogenous enkephalins and endorphins to stimulate the immune system
US4771769A (en) 1982-12-20 1988-09-20 Schering Corporation Hand held metered spray dispenser
JPS59163313A (ja) 1983-03-09 1984-09-14 Teijin Ltd 経鼻投与用ペプチドホルモン類組成物
US4481191A (en) 1983-03-30 1984-11-06 The Regents Of The University Of California Method for controlling blood pressure
US4959358A (en) 1983-06-06 1990-09-25 Beth Israel Hospital Assn. Drug administration
US4548922A (en) 1983-06-06 1985-10-22 Beth Israel Hospital Drug administration
US4746508A (en) 1983-06-06 1988-05-24 Beth Israel Hospital Assn. Drug administration
US4699136A (en) 1983-12-22 1987-10-13 Krauser Robert S Method and apparatus for treating ailments
US5082658A (en) 1984-01-16 1992-01-21 Genentech, Inc. Gamma interferon-interleukin-2 synergism
JPS60161924A (ja) 1984-02-01 1985-08-23 Fujisawa Pharmaceut Co Ltd 肺吸収用組成物
US4590003A (en) 1984-03-23 1986-05-20 Oncogen Platelet related growth regulator
US4645828A (en) 1984-03-23 1987-02-24 Oncogen Platelet related growth regulator
ZA846192B (en) 1984-08-09 1986-03-26 Merck Patent Gmbh Immunotherapeutic polypeptide agents
DE3470380D1 (en) * 1984-08-09 1988-05-19 Inge Brugger Nebulizer
GB2172590A (en) * 1985-03-19 1986-09-24 Emhart Ind Mould arrangement of a glassware forming machine
JPS6248634A (ja) 1985-07-23 1987-03-03 Mochida Pharmaceut Co Ltd 新規アミノ酸組成物、その製造方法及び該アミノ酸組成物を含有する医療組成物
DE3779221D1 (de) * 1986-08-19 1992-06-25 Genentech Inc Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und -zytokinen.
US4710305A (en) 1986-12-29 1987-12-01 Conoco Inc. Processes and oxidizing agents for oxidizing sulfide ion to innocuous, soluble sulfur species
CA2082951C (fr) 1991-03-15 1999-12-21 Robert M. Platz Administration au niveau pulmonaire du facteur stimulant la proliferation des granulocytes
US5354934A (en) 1993-02-04 1994-10-11 Amgen Inc. Pulmonary administration of erythropoietin
DE10006167B4 (de) * 2000-02-11 2009-07-23 Abb Schweiz Ag Leistungsschalter
DE10032433A1 (de) * 2000-07-04 2002-01-17 H A N D Gmbh Verfahren zur Bodenraumüberwachung

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7744925B2 (en) 1994-12-02 2010-06-29 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US7780991B2 (en) 1994-12-02 2010-08-24 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US7785631B2 (en) 1994-12-02 2010-08-31 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US8168223B1 (en) 1997-09-29 2012-05-01 Novartis Pharma Ag Engineered particles and methods of use
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US9439862B2 (en) 2000-05-10 2016-09-13 Novartis Ag Phospholipid-based powders for drug delivery
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside
US10507227B2 (en) 2014-04-15 2019-12-17 The Hospital For Sick Children Cationic antimicrobial peptides

Also Published As

Publication number Publication date
EP0257956A3 (en) 1989-04-19
ES2032831T3 (es) 1993-03-01
ATE76311T1 (de) 1992-06-15
US6099517A (en) 2000-08-08
CA1292182C (fr) 1991-11-19
EP0257956B1 (fr) 1992-05-20
JP2573959B2 (ja) 1997-01-22
US6402733B1 (en) 2002-06-11
JPS6351868A (ja) 1988-03-04
US20020193730A1 (en) 2002-12-19
GR3005238T3 (fr) 1993-05-24
ES2032831T5 (es) 2001-02-16
EP0257956A2 (fr) 1988-03-02
DE3779221D1 (de) 1992-06-25

Similar Documents

Publication Publication Date Title
EP0257956B2 (fr) Usage de facteurs de croissance et de cytocines polypeptides pour fabriquer un dispositif et une dispersion
KR100652532B1 (ko) 유동 저항이 조절된 에어로졸화 활성 약물의 송달
KR100620338B1 (ko) 에어로졸형 활성 제제 전달 방법
US7300919B2 (en) Pulmonary delivery of active fragments of parathyroid hormone
US20110268668A1 (en) Process for nebulizing aqueous compositions containing highly concentrated insulin
US20030064032A1 (en) Process for nebulizing aqueous compositions containing highly concentrated insulin
US20020127188A1 (en) Composition for pulmonary administration comprising a drug and a hydrophobic amino acid
JP2002500192A (ja) ＡｓｐＢ２８−ヒトインシュリンの投与方法
AU2003218306A1 (en) Method for administration of growth hormone via pulmonary delivery
WO2002094283A2 (fr) Utilisation de phospholipides dans le traitement de maladie degenerative du poumon et pour ameliorer l'administration de medicaments
US20050163725A1 (en) Method for administration of growth hormone via pulmonary delivery
CZ20003075A3 (cs) Způsob podávání aktivního činidla, způsob podávání inzulínu, zařízení pro zvýšení biologické dostupnosti aktivního činidla a zařízení pro podávání inzulínu

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

17P Request for examination filed

Effective date: 19890818

17Q First examination report despatched

Effective date: 19901218

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

REF Corresponds to:

Ref document number: 76311

Country of ref document: AT

Date of ref document: 19920615

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3779221

Country of ref document: DE

Date of ref document: 19920625

ITF It: translation for a ep patent filed

Owner name: MODIANO & ASSOCIATI S.R.L.

ET Fr: translation filed
PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

REG Reference to a national code

Ref country code: GR

Ref legal event code: FG4A

Free format text: 3005238

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2032831

Country of ref document: ES

Kind code of ref document: T3

26 Opposition filed

Opponent name: SCHERING CORPORATION

Effective date: 19930218

NLR1 Nl: opposition has been filed with the epo

Opponent name: SCHERING CORPORATION

EPTA Lu: last paid annual fee
EAL Se: european patent in force in sweden

Ref document number: 87307276.3

APAC Appeal dossier modified

Free format text: ORIGINAL CODE: EPIDOS NOAPO

APAC Appeal dossier modified

Free format text: ORIGINAL CODE: EPIDOS NOAPO

APAE Appeal reference modified

Free format text: ORIGINAL CODE: EPIDOS REFNO

APAC Appeal dossier modified

Free format text: ORIGINAL CODE: EPIDOS NOAPO

PLAW Interlocutory decision in opposition

Free format text: ORIGINAL CODE: EPIDOS IDOP

RTI2 Title (correction)

Free format text: USE OF POLYPEPTIDE GROWTH FACTORS AND CYTOKINES FOR THE MANUFACTURE OF A DEVICE AND OF A DISPERSION

PUAH Patent maintained in amended form

Free format text: ORIGINAL CODE: 0009272

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: PATENT MAINTAINED AS AMENDED

27A Patent maintained in amended form

Effective date: 20001122

AK Designated contracting states

Kind code of ref document: B2

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

RIC2 Information provided on ipc code assigned after grant

Free format text: 7A 61K 38/18 A, 7A 61K 38/19 B

REG Reference to a national code

Ref country code: CH

Ref legal event code: AEN

Free format text: MAINTIEN DU BREVET DONT L'ETENDUE A ETE MODIFIEE

ITF It: translation for a ep patent filed

Owner name: MODIANO & ASSOCIATI S.R.L.

NLR2 Nl: decision of opposition
REG Reference to a national code

Ref country code: ES

Ref legal event code: DC2A

Kind code of ref document: T5

Effective date: 20010116

ET3 Fr: translation filed ** decision concerning opposition
NLR3 Nl: receipt of modified translations in the netherlands language after an opposition procedure
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

APAH Appeal reference modified

Free format text: ORIGINAL CODE: EPIDOSCREFNO

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20060714

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20060803

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20060808

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20060810

Year of fee payment: 20

Ref country code: DE

Payment date: 20060810

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20060811

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20060815

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20060816

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20060822

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20060831

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20061013

Year of fee payment: 20

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

NLV7 Nl: ceased due to reaching the maximum lifetime of a patent

Effective date: 20070818

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20070820

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070817

BE20 Be: patent expired

Owner name: *GENENTECH INC.

Effective date: 20070818

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070820

Ref country code: NL

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20070818

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20060804

Year of fee payment: 20